Myocardial infarct is an irreversible injury (Ho K. K., Anderson K. M., Kannel W. B., Grossman W., Levy D., Circulation, 1993; 88: 107-115). Ischemic heart diseases are the cause of death responsible for 50% of all cardiovascular system-related deaths and the major cause of congestive heart failure. The 1-year mortality observed in patients who are diagnosed as having congestive heart failure and eventually die from chronic heart disease is 20% (American Heart Association, Dallas, Tex.: American Heart Association; 2001). Most therapies currently available to clinicians can significantly improve the prognosis of patients suffering from acute myocardial infarct. Angioplasty and thrombolytic agents may remove the cause of the acute myocardial infarct, though the period of time from the onset of occlusion to reperfusion determines the degree of irreversible myocardial injury (Ryan T. J., Antman E. M., Brooks N. H., Califf R. M., Hillis L. D., Hiratzka L. F., Rapaport E., Riegel B., Russell R. O., Smith E. E. III, Weaver W. D., Gibbons R. J., Alpert J. S., Eagle K. A., Gardner T. J., Garson A. Jr., Gregoratos G., Ryan T. J., Smith S. C. Jr., J. Am. Coll. Cardiol., 1999; 34: 890-911). No clinically used pharmaceutical agent or treatment has an efficacy on the replacement of myocardial scars with functional contraction tissue. There is a demand for a novel therapy for regenerating normal cardiomyocytes.
Cardiomyoplasty has been proposed as a surgical method for improving the function of the left ventricle (LV) of a patient suffering from congestive heart failure, however, the effect thereof on the cardiac function remains unclear (Corin W. J., George D. T., Sink J. D. et al., J. Thorac. Cardiovasc. Surg., 1992, 104:1662-1671; Kratz J. M., Johnson W. S., Mukherjee R. et al., J. Thorac. Cardiovasc. Surg., 1994, 107:868-878; Carpentier A., Chachques J. C., Lancet, 1985, 8840:1267; and Hagege A. A., Desnos M., Chachques J. C. et al., Preliminary report: follow-up after dynamic cardiomyoplasty, Lancet, 1990, 335:1122-1124). Recently, implantation of a biologically modified heart graft, in which a biodegradable scaffold is used, has been proposed as another novel approach. However, the graft hardly attaches to the myocardium, resulting in the least possible benefit for the improvement of the cardiac function (Leor J., Etzion S. A., Dar A. et al., Circulation, 2000; 102 [suppl. III] III-56-III-61; and Li R. K., Jia Z. Q., Weisel R. D. et al., Circulation, 1999; 100 [suppl II]: II-63-II-69). The histological and electrical integration of biologically modified heart tissue and a recipient heart may be crucial for the regeneration of impaired myocardium.
The recent development of tissue engineering is expected to make possible the production of a functional heart tissue using a novel technique, in which cell sheets are three-dimensionally layered without any biodegradable substitute for extracellular matrices (ECM) (Okano T., Yamada N., Sakai H., Sakurai Y., J. Biomed. Mater. Res., 1993; 27:1243-1251). In this novel technique, both intracellular adhesion and adhesion proteins within a confluently cultured cell monolayer are fully maintained. Endogenous ECM supporting a cell sheet whose base portion has been collected by a collecting method (Kushida A., Yamato M., Konno C., Kikuchi A., Sakurai Y., Okano T., J. Biomed. Mater. Res., 45:355-362, 1999) plays an important role as an adhesion factor for the integration to the recipient heart. Further, the cardiomyocyte sheet is a pulsating 3-D heart construct which transmits electricity (Shimizu T., Yamato M., Akutsu T. et al., Circ. Res., Feb. 22, 2002, 90(3):e40). However, it is unknown whether or not cardiomyocyte sheets retain their functions after in vivo implantation.
The recent progress in tissue engineering has the potential of providing an implantable functional tissue comprising various cells and an extracellular matrix.
Implantation of organs (e.g., heart, blood vessel, etc.) using an exogenous tissue is mainly hindered by immunological rejections. Changes occurring in allografts and xenografts were first described 90 or more years ago (Carrel A., 1907, J. Exp. Med. 9:226-228; Carrel A., 1912, J. Exp. Med. 9:389-392; Calne R. Y., 1970, Transplant Proc. 2:550; and Auchincloss 1988, Transplantation 46:1). Rejection to artery grafts pathologically leads either to enlargement (up to rupture) or occlusion of the grafts. The former is caused by decomposition of extracellular matrices, while the latter is caused by proliferation of cells in a blood vessel (Uretsky B. F., Mulari S., Reddy S., et al., 1987, Circulation 76:827-834). Such grafts are often made from non-biological materials which lead to adverse effects.
Recently, cell implantation has attracted attention as a therapy utilizing biological material. However, the implantation of human myoblasts into the infarcted heart has the following drawbacks: 1. damage and loss of implantation cells; 2. tissue injury of the recipient heart during implantation; 3. tissue supply efficiency to the recipient heart; 4. occurrence of arrhythmia; 5. difficulty in treating the entirety of the infarcted site; and the like. Therefore, cell implantation cannot be said to be very successful.
Myocardium-derived sheets have been developed. Typically, autologous myocardium is required for the myocardium-derived sheet in view of immune reactions. Therefore, the applications of the sheet are limited.
Accordingly, there is a keen demand for a prosthetic tissue, a three-dimensional structure, or a sheet capable of withstanding implantation operations, being used in actual operations, and being produced by culture.